The onset of experimental diabetic neuropathy, as manifested by decreased peripheral nerve conduction velocity, is accompanied by reduced levels and uptake of nerve myo-inositol. Recent evidence suggests that myo-inositol administration to diabetic animals improves conduction velocity and restores diminished nerve sodium-potassium ATPase activity. Myo-inositol seems likely to exert its effects through its metabolic products, the phosphoinositides, which have long been candidates for a role in nerve impulse conduction. We have established that a highly reproducible, specific and appreciable increment in P32 labeling in vitro of nerve polyphosphoinositides (PPI), especially phosphatidylinositol-4,5-bisphosphate (PIP2), occurs in sciatic nerve from rats with acute and chronic streptozotocin diabetes and that this phenomenon can be prevented or reversed by insulin treatment. We propose to continue investigations of the hypothesis that these metabolic alterations are integral to the development of peripheral nerve functional deficits. Specifically, we will: 1) determine whether abnormal PPI metabolism is characteristic of several spontaneously diabetic rodent models, namely the obese mouse (C57BL/ks(db/db), the BB Wistar rat and the Wistar fatty rat; 2) evaluate whether the changes are an outcome of the diabetic state, or are characteristic generally of distal neuropathies by examination of phosphoinositide metabolism in galactose and acrylamide neuropathies and in early Wallerian degeneration; 3) ascertain whether sorbinil, an aldose reductase inhibitor, can prevent or reverse the alterations when present in vitro or administered in vivo; 4) attempt to elucidate a possible enzymatic defect in nerve responsible for the effect by: a) assay of phosphoinositide-metabolizing enzymes and characterization of a putative membrane-bound PPI phosphodiesterase, active against endogenous PIP2; b) following the metabolic fate of prelabeled PPI in resting and depolarizing conditions; c) measurement of PPI and D-inositol-1-phosphate levels; 5) since altered PIP2 metabolism, especially phosphodiesteratic hydrolysis, could affect diacylglycerol-activated protein kinase C, determine whether qualitative and quantitative differences exist in the pattern of phosphorylated proteins in normal as compared to diabetic nerve. The basic knowledge gathered will furnish useful information concerning the etiology of experimental diabetic neuropathy and may have relevance to the origins and pathology of the human disease.